Mitochondrial Uncoupling Prodrug as a Translational Therapy for TBI

创伤性脑损伤(TBI)会导致认知障碍，在中到重度后可能会持续很长时间 TBI。目前，还没有FDA批准的疗法来治疗创伤性脑损伤和 提高复苏率。大量实验证据表明，线粒体功能障碍可能是一种 脑损伤的神经病理学中的关键环节。我们之前已经针对生物能量损伤进行了 线粒体导向疗法，包括温和的线粒体解偶联剂，已表明 具有神经保护作用。这些解偶联分子促进了质子从线粒体内膜上的移动。 因此线粒体膜电位(∆ψ)降低。而当 线粒体的完全解偶联将是有害的，我们已经公布的数据表明，瞬时或 “轻度解偶联”在临床前脑损伤模型中提供神经保护。最近，我们展示了一种前药 2，4-二硝基苯酚(DNP)，MP201，一种线粒体解偶联剂，具有更好的药效学特性，包括 更高的耐受性和更长的消除时间，拯救急性线粒体生物能量学，减少氧化 损伤，增加脑源性神经营养因子(BDNF)，具有神经保护作用。我们假设 MP201治疗干预的最佳剂量和时机是对病灶后跨物种的神经保护 脑挫伤。我们拟议的研究将探索MP201管理如何改善急性、 纵向的和慢性的结果，与关键的生物标记物配对，包括血小板生理和 神经化学特征。为了实现这一目标，我们将使用跨多个机构的创新技术来评估 猪和小鼠脑外伤模型中突触和非突触线粒体。此外，我们还将延长 我们的发现是通过测量纵向皮质形态(T2/DTI扫描)来检查治疗效果， 神经代谢物图谱(MRS扫描)、血小板特征(作为一种新的生物标志物和生物传感器)和认知 行为。最后，我们将探索长期神经保护背后的潜在机制 MP201，检测脑源性神经营养因子水平及线粒体修复情况。具有较强的前期数据和利用能力 许多创新的和临床相关的技术，我们预计这项建议将产生突破性的 数据。总体而言，这项提案将突出MP201高度可翻译的治疗方法，以减轻 TBI。

Traumatic brain injury (TBI) results in cognitive impairment, which can be long-lasting after moderate to severe TBI. Currently, there are no FDA-approved therapeutics to treat the devastating consequences of TBI and improve recovery. A wealth of experimental evidence shows that mitochondrial dysfunction is poised to be a pivotal link in the neuropathology of brain injury. We previously have targeted bioenergetic impairment with mitochondria-directed therapeutics, including mild mitochondrial uncouplers, which have shown to be neuroprotective. These uncouplers facilitate the movement of protons from the mitochondrial inner-membrane space into the mitochondrial matrix, thereby reducing the mitochondrial membrane potential (∆ψ). While complete uncoupling of mitochondria would be detrimental, we have published data showing that transient or “mild uncoupling” confers neuroprotection in preclinical models of TBI. Recently, we demonstrated that a prodrug of 2,4-dinitrophenol (DNP), MP201, a mitochondrial uncoupler with better pharmacodynamic properties including higher tolerability and extended elimination time, rescues acute mitochondrial bioenergetics, reduces oxidative damage, increases brain-derived neurotropic factor (BDNF) and is neuroprotective. We hypothesize that the optimal dosage and timing of therapeutic intervention of MP201 is neuroprotective across species following focal contusion brain injury. Our proposed studies will explore how MP201 administration can improve acute, longitudinal, and chronic outcomes, paired with critical biomarkers, including platelet physiology and neurochemical profiles. To achieve this, we will use innovative techniques across multiple institutions to assess synaptic and non-synaptic mitochondria in both porcine and murine models of TBI. Additionally, we will extend our findings to examine therapeutic efficacy, measuring longitudinal cortical morphology (T2/DTI scanning), neurometabolite profiles (MRS scanning), platelet signature (as a novel biomarker and biosensor), and cognitive behavior. Finally, we will explore the underlying mechanism behind the long-term neuroprotection imparted by MP201 after TBI, examining BDNF levels and mitochondrial restoration. With strong preliminary data and utilizing many innovative and clinically-relevant techniques, we anticipate this proposal will generate ground-breaking data. Overall, this proposal will highlight highly translatable therapy by MP201 to alleviate negative outcomes of TBI.